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| United States Patent |
6,153,225
|
|
Lee
, et al.
|
November 28, 2000
|
Injectable formulations of nanoparticulate naproxen
Abstract
Described are an injectable formulation of nanoparticulate naproxen that
produces minimal or no pain or burning sensation upon administration, and
methods of making and using such a formulation. The injectable formulation
comprises nanoparticulate naproxen having a povidone polymer adsorbed on
the surface thereof in an amount sufficient to maintain an effective
average particle size of less than about 600 nm.
| Inventors:
|
Lee; Robert (Gilbertsville, PA);
De Castro; Lan (Montclair, NJ)
|
| Assignee:
|
Elan Pharma International Limited (Shannon, IE)
|
| Appl. No.:
|
154422 |
| Filed:
|
August 13, 1998 |
| Current U.S. Class: |
424/501; 264/4.1; 264/4.33; 264/4.7; 428/402.21 |
| Intern'l Class: |
A61K 009/50; B01J 013/02; B32B 005/16 |
| Field of Search: |
424/501
264/4.1,4.33,4.7
428/402.21
|
References Cited
U.S. Patent Documents
| 3904682 | Sep., 1975 | Fried et al.
| |
| 4009197 | Feb., 1977 | Fried et al.
| |
| 4780320 | Oct., 1988 | Baker.
| |
| 4888178 | Dec., 1989 | Rotini et al.
| |
| 4919939 | Apr., 1990 | Baker.
| |
| 4940588 | Jul., 1990 | Sparks et al.
| |
| 5145684 | Sep., 1992 | Liversidge et al.
| |
| 5200193 | Apr., 1993 | Radebaugh et al.
| |
| 5354556 | Oct., 1994 | Sparks et al.
| |
| 5462747 | Oct., 1995 | Radebaugh et al.
| |
| 5480650 | Jan., 1996 | Marchi et al.
| |
| 5510118 | Apr., 1996 | Bosch et al.
| |
| 5770222 | Jun., 1998 | Unger et al. | 424/450.
|
| Foreign Patent Documents |
| 2 046 094 | Nov., 1980 | EP.
| |
| 0 577 215 | Jan., 1994 | EP.
| |
| 0 463 228 | Jan., 1998 | EP.
| |
Other References
The Merck Index, 10.sup.th Edition, pp. 920 (Merck & Co., Rahway, NJ,
1983).
American Family Physician, Mar. 1997.
Marsala et al., "Treatment of Acute Pain of Ureteral and Biliary Colic with
Naproxen Sodium Administered by the Parenteral Route," Int. J. Clin.
Pharmacol. Res., 6:495-500 (1986) (IM an IV injections of naproxen).
L. Kvarnes, "Naproxen Sodium Versus Pentazocine in Treating Postoperative
Pain," Curr. Ther. Res., Clin. Exp., 46:259-268 (1989) (IM injections of
naproxen).
The Merck Index, 10.sup.th Edition, pp. 1106 (Merck & Co., Rahway, NJ,
1983).
|
Primary Examiner: Azpuru; Carlos A.
Attorney, Agent or Firm: Foley & Lardner
Claims
We claim:
1. A nanoparticulate injectable pharmaceutical composition comprising: (1)
naproxen particles having an effective average particle size of less than
about 600 nm; (2) a povidone polymer adsorbed on the surface of the
naproxen particles, wherein the povidone polymer has a molecular weight of
about 40,000 daltons or less; and (3) a pharmaceutically acceptable
carrier.
2. The composition of claim 1, wherein the effective average particle size
of the naproxen particles is less than about 450 nm.
3. The composition of claim 1, wherein the effective average particle size
of the naproxen particles is selected from the group consisting of less
than about 400 nm, less than about 300 nm, less than about 250 nm, and
less than about 100 nm.
4. The composition of claim 1, wherein the povidone polymer is present in
an amount of about 0.1 to about 50% (w/w) based on the total weight of the
naproxen and povidone polymer.
5. The composition of claim 1, wherein the naproxen is present in an amount
of about 5.0 to about 50% (w/w), by weight.
6. A method of treating a mammal comprising administering to the mammal an
effective amount of a nanoparticulate injectable pharmaceutical
composition comprising: (1) naproxen particles having an effective average
particle size of less than about 600 nm; (2) a povidone polymer adsorbed
on the surface of the naproxen particles, wherein the povidone polymer has
a molecular weight of about 40,000 daltons or less; and (3) a
pharmaceutically acceptable carrier.
7. The method of claim 6, wherein the effective average particle size of
the naproxen particles is less than about 450 nm.
8. The method of claim 7, wherein the effective average particle size of
the naproxen particles is selected from the group consisting of less than
about 400 nm, less than about 300 nm, less than about 250 nm, and less
than about 100 nm.
9. The method of claim 6, wherein the povidone polymer has a molecular
weight of about 40,000 daltons.
10. The method of claim 6, wherein the povidone polymer has a molecular
weight of less than about 40,000 daltons.
11. A method of preparing a nanoparticulate injectable pharmaceutical
composition that produces minimal or no pain or irritation upon
administration, wherein the composition comprises: (1) naproxen particles
having an effective average particle size of less than about 600 nm; (2) a
povidone polymer adsorbed on the surface of the naproxen particles,
wherein the povidone polymer has a molecular weight of about 40,000
daltons or less; and (3) a pharmaceutically acceptable carrier, wherein
the method comprises:
(a) dispersing the naproxen particles in a liquid dispersion medium
comprising a povidone polymer; and
(b) mechanically reducing the particle size of the naproxen to an effective
average particle size of less than about 600 nm.
12. The method of claim 11, wherein the effective average particle size of
the naproxen particles is less than about 450 nm.
13. The method of claim 12, wherein the effective average particle size of
the naproxen particles is selected from the group consisting of less than
about 400 nm, less than about 300 nm, less than about 250 nm, and less
than about 100 nm.
14. A method of preparing a nanoparticulate injectable pharmaceutical
composition comprising: (1) naproxen particles having an effective average
particle size of less than about 600 nm; (2) a povidone polymer adsorbed
on the surface of the naproxen particles, wherein the povidone polymer has
a molecular weight of about 40,000 daltons or less; and (3) a
pharmaceutically acceptable carrier, wherein the method comprises:
(a) dispersing the naproxen particles in a liquid dispersion;
(b) mechanically reducing the particle size of the naproxen to an effective
average particle size of less than about 600 nm; and
(c) adding a povidone polymer to the dispersion of naproxen particles.
15. The method of claim 14, wherein the effective average particle size of
the naproxen particles is less than about 450 nm.
16. The method of claim 15, wherein the effective average particle size of
the naproxen particles is selected from the group consisting of less than
about 400 nm, less than about 300 nm, less than about 250 nm, and less
than about 100 nm.
17. The composition of claim 1, wherein the pH of the nanoparticulate
composition is between about 6 to about 7.
18. The method of claim 6, wherein the pH of the nanoparticulate
composition is between about 6 to about 7.
19. The method of claim 11, wherein the pH of the nanoparticulate
composition is between about 6 to about 7.
20. The method of claim 14, wherein the pH of the nanoparticulate
composition is between about 6 to about 7.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is directed to an injectable formulation of
nanoparticulate naproxen that produces minimal or no intramuscular pain or
burning sensation upon administration, methods of making such a
formulation, and methods of using such a formulation.
2. Description of the Related Art
Naproxen, also known as 6-methoxy-.alpha.-methyl-2-napthalene-acetic acid
and d-2(6-methoxy-2-naphthyl)propionic acid, is a well-known
anti-inflammatory, analgesic, and antipyretic agent. It has been approved
in many countries around the world for almost two decades and has a very
safe risk-benefit profile. It is sold under the trade names ALEVE.RTM.,
ANAPROX.RTM., NAPROSYN.RTM., and SYNFLEX.RTM. (all available from Syntex
Chemicals, Inc.). See The Merck Index, 10.sup.th Edition, pp. 6274 (Merck
& Co., Rahway, N.J., 1983).
Naproxen, which is highly water insoluble, i.e., less than 10 mg/ml, has
the following chemical structure:
##STR1##
Naproxen is a non-steroidal anti-inflammatory drug (NSAID) often used to
relieve the inflammation, swelling, stiffness, and joint pain associated
with rheumatoid arthritis, osteoarthritis (the most common form of
arthritis), juvenile arthritis, ankylosing spondylitis (spinal arthritis),
tendinitis, bursitis, and acute gout. In addition, it is used to treat
pain associated with menstrual periods, migraine headaches, and other
types of mild to moderate pain.
Naproxen acts by suppressing the production of prostaglandins, which are
hormone-like substances that act on local tissues to produce pain and
inflammation. Its pharmaceutical forms of delivery include tablets,
capsules, and liquids. Delivery characteristics and forms are disclosed
in, for example, U.S. Pat. Nos. 3,904,682; 4,009,197; 4,780,320;
4,888,178; 4,919,939; 4,940,588; 4,952,402; 5,200,193; 5,354,556;
5,462,747; and 5,480,650, all of which are specifically incorporated by
reference. The synthesis of naproxen is described in U.S. Pat. Nos.
3,904,682 and 4,009,197.
Naproxen is a more potent pain reliever than aspirin, especially for
menstrual cramps, toothaches, minor arthritis, and injuries accompanied by
inflammation, such as tendinitis. The naproxen sodium salt is specifically
indicated in the treatment of various types of acute and very high
intensity pain because it induces a rapid and sustained remission. In
addition, it is possible to obtain a good analgesic effect with few
administrations, due to naproxen's particular pharmacokinetics. Tablet
formulations of naproxen were approved for OTC ("over the counter" as
compared to prescription) marketing by the U.S. Food and Drug
Administration in 1994.
Because of naproxen's low solubility, it is generally formulated for oral
administration. However, oral administration of naproxen frequently
results in gastrointestinal irritation. All NSAIDs produce
gastrointestinal symptoms to some degree upon oral administration. Such
symptoms most commonly are constipation, gastric burns, diarrhea,
stomatitis, dyspepsia, nausea, vomiting, upper abdominal pain, and
heartburn. Oral administration may also lead to an ulcer or bleeding from
the stomach or duodenum.
Gastrointestinal irritation resulting from oral administration of an NSAID
can be significant. Numerous literature articles detail the severity of
gastric irritation caused by NSAID compositions. For example, one report
states that between 10,000 and 20,000 people in Canada each year are
hospitalized with major gastro-intestinal bleeding caused by oral
ingestion of NSAIDs, with effects resulting in death for at least 1,000 of
these patients. See Marketplace, Oct. 24, 1996. Yet another reference
states that gastrointestinal complications of NSAID use may be responsible
for over 10,000 deaths each year. See American Family Physician, March
1997.
Injectable formulations of naproxen are preferable over oral administration
forms for several reasons. First, such formulations can lessen or
eliminate side effects of gastro-intestinal irritation. Second,
intravenous (IV) or intramuscular (IM) administration of a drug results in
a significantly shorter response time as compared to oral administration.
Moreover, injectable formulations of pain medication are also preferable
for post-operative health care, where oral administration may not be
feasible. Injectable formulations of naproxen are particularly preferred,
as naproxen is not addictive, in contrast to other injectable formulations
of drugs, such as morphine and ketorolac (Toradol.RTM.).
Injectable formulations of naproxen have been used prior to the present
invention. See Marsala et al., "Treatment of Acute Pain of Ureteral and
Biliary Colic with Naproxen Sodium Administered by the Parenteral Route,"
Int. J. Clin. Pharmacol. Res., 6:495-500 (1986) (IM and IV injections of
naproxen); L. Kvarnes, "Naproxen Sodium Versus Pentazocine in Treating
Postoperative Pain," Curr. Ther. Res., Clin. Exp., 46:259-268 (1989) (IM
injections of naproxen). However, injectable naproxen formulations arc
difficult to formulate due to the low solubility of naproxen. Moreover,
current injectable formulations of naproxen are undesirable because they
produce intense pain and/or a burning sensation upon administration. Such
pain is counter-productive, particularly as the patient to be treated is
generally already suffering from intense pain. Thus, the pain upon
administration interferes with patient treatment, and has led to the use
of alternative, but less desirable, injectable pain medications.
There is currently a need for a safe and effective injectable formulation
of naproxen that produces minimal or no pain or burning sensation upon
administration. In addition, there is a need in the art for methods of
making and methods of using such naproxen formulations. The present
invention satisfies these needs.
SUMMARY OF THE INVENTION
The present invention is directed to the surprising and unexpected
discovery of a new injectable formulation of naproxen that produces
minimal or no pain or burning sensation upon administration. The
injectable formulation comprises nanoparticulate naproxen having a
povidone polymer adsorbed on the surface thereof in an amount sufficient
to maintain an effective average particle size of less than about 600 nm.
Preferably, the effective average particle size of the nanoparticulate
naproxen is less than about 450 nm, more preferably less than about 300
nm, even more preferably less than about 250 nm, and most preferably less
than about 100 nm. Nanoparticulate compositions were first described in
U.S. Pat. No. 5,145,684 ("the '684 patent"), which is specifically
incorporated herein by reference.
The invention provides for compositions comprising high naproxen
concentrations in low injection volumes, with rapid drug dissolution upon
administration.
In another aspect of the invention there is provided a method of preparing
injectable nanoparticulate naproxen formulations. The method comprises:
(1) dispersing naproxen in a liquid dispersion medium comprising a
povidone polymer with a molecular weight of less than about 40,000
daltons; and (2) mechanically reducing the particle size of the naproxen
to an effective average particle size of less than about 600 nm.
Preferably, the pH of the liquid dispersion medium is maintained within
the range of from about 3 to about 8 during the size reduction process.
Yet another aspect of the present invention provides a method of treating a
mammal requiring anti-inflammatory, analgesic, or antipyretic treatment
comprising administering to the mammal the above-described injectable
nanoparticulate naproxen formulation.
It is to be understood that both the foregoing general description and the
following detailed description are exemplary and explanatory and are
intended to provide further explanation of the invention as claimed. Other
objects, advantages, and novel features will be readily apparent to those
skilled in the art from the following detailed description of the
invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to the surprising and unexpected
discovery of a new injectable formulation of naproxen that produces
minimal or no pain or burning sensation upon administration. The
injectable composition comprises nanoparticulate naproxen having a
povidone polymer with a molecular weight of less than about 40,000 daltons
adsorbed on the surface thereof in an amount sufficient to maintain an
effective average particle size of less than about 600 nm. Preferably, the
effective average particle size of the nanoparticulate naproxen is less
than about 450 nm, more preferably less than about 300 nm, even more
preferably less than about 250 nm, and most preferably less than about 100
nm.
Naproxen has a pKa of 4.4. Below its pKa of 4.4, the solubility of naproxen
is about 20 micrograms/ml. However, above a pKa of 4.4, the solubility of
naproxen is about 3 mg/ml. It is preferred that the nanoparticulate
naproxen/povidone polymer pharmaceutical formulation of the invention has
a pH of between about 6 to about 7.
In human therapy, it is important to provide a naproxen dosage form that
delivers the required therapeutic amount of the drug in vivo, and that
renders the drug bioavailable in a rapid and constant manner. The
injectable nanoparticulate naproxen formulations of the present invention
satisfies these needs.
Povidone Polymers
Povidone polymers, also known as polyvidon(e), povidonum, PVP, and
polyvinylpyrrolidone, are sold under the trade names Kollidon.RTM. (BASF
Corp.) and Plasdone.RTM. (ISP Technologies, Inc.). They are polydisperse
macromolecular molecules, with a chemical name of
1-ethenyl-2-pyrrolidinone polymers and 1-vinyl-2-pyrrolidinone polymers.
Povidone polymers are produced commercially as a series of products having
mean molecular weights ranging from about 10,000 to about 700,000 daltons.
To be useful as a surface modifier for a drug compound to be administered
to a mammal, the povidone polymer must have a molecular weight of less
than about 40,000 daltons, as a molecular weight of greater than 40,000
daltons would have difficulty clearing the body.
Povidone polymers are prepared by, for example, Reppe's process,
comprising: (1) obtaining 1,4-butanediol from acetylene and formaldehyde
by the Reppe butadiene synthesis; (2) dehydrogenating the 1,4-butanediol
over copper at 200.degree. to form .gamma.-butyrolactone; and (3) reacting
.gamma.-butyrolactone with ammonia to yield pyrrolidone. Subsequent
treatment with acetylene gives the vinyl pyrrolidone monomer.
Polymerization is carried out by heating in the presence of H.sub.2 O and
NH.sub.3. See The Merck Index, 10.sup.th Edition, pp. 7581 (Merck & Co.,
Rahway, N.J., 1983).
The manufacturing process for povidone polymers produces polymers
containing molecules of unequal chain length, and thus different molecular
weights. The molecular weights of the molecules vary about a mean or
average for each particular commercially available grade. Because it is
difficult to determine the polymer's molecular weight directly, the most
widely used method of classifying various molecular weight grades is by
K-values, based on viscosity measurements. The K-valucs of various grades
of povidone polymers represent a function of the average molecular weight,
and are derived from viscosity measurements and calculated according to
Fikentscher's formula.
The weight-average of the molecular weight, Mw, is determined by methods
that measure the weights of the individual molecules, such as by light
scattering. Table 1 provides molecular weight data for several
commercially available povidone polymers, all of which are soluble.
TABLE 1
______________________________________
Mv Mw Mn
Povidone K-Value (Daltons)**
(Daltons)**
(Daltons)**
______________________________________
Plasdone C-15 .RTM.
17 .+-. 1
7,000 10,500 3,000
Plasdone C-30 .RTM.
30.5 .+-. 1.5
38,000 62,500* 16,500
Kollidon 12 PF .RTM.
11-14 3,900 2,000-3,000
1,300
Kollidon 17 PF .RTM.
16-18 9,300 7,000- 2,500
11,000
Kollidon 25 .RTM.
24-32 25,700 28,000- 6,000
34,000
______________________________________
*Because the molecular weight is greater than 40,000 daltons, this
povidone polymer is not useful as a surface stabilizer for a drug compoun
to be administered parenterally (i.e., injected).
**Mv is the viscosityaverage molecular weight, Mn is the numberaverage
molecular weight, and Mw is the weight average molecular weight. Mw and M
were determined by light scattering and ultracentrifugation, and Mv was
determined by viscosity measurements.
Based on the data provided in Table 1, exemplary preferred commercially
available povidone polymers include, but are not limited to, Plasdone
C-15.RTM., Kollidon 12 PF.RTM., Kollidon 17 PF.RTM., and Kollidon 25.RTM..
Injectable Nanoparticulate Naproxen Formulations
The invention provides injectable nanoparticulate naproxen formulations
that can comprise high drug concentrations in low injection volumes, with
rapid drug dissolution upon administration. Preferred compositions
comprise, based on % w/w:
______________________________________
naproxen 5-50%
povidone polymer
0.1-50%
preservatives 0.05-0.25%
pH adjusting agent
pH about 6 to about 7
water for injection
q.s.
______________________________________
Exemplary preservatives include methylparaben (about 0.18% based on % w/w),
propylparaben (about 0.02% based on % w/w), phenol (about 0.5% based on %
w/w), and benzyl alcohol (up to 2% v/v). An exemplary pH adjusting agent
is sodium hydroxide, and an exemplary liquid carrier is sterile water for
injection. Other useful preservatives, pH adjusting agents, and liquid
carriers are well-known in the art.
Methods of Making Injectable Naproxen Formulations
In another aspect of the invention there is provided a method of preparing
the injectable nanoparticulate naproxen formulations of the invention. The
method comprises: (1) dispersing naproxen in a liquid dispersion medium
comprising a povidone polymer with a molecular weight of less than about
40,000 daltons; and (2) mechanically reducing the particle size of the
naproxen to an effective average particle size of less than about 600 nm.
Preferably, the effective average particle size of the nanoparticulate
naproxen is less than about 450 nm, more preferably less than about 300
nm, even more preferably less than about 250 nm, and most preferably less
than about 100 nm. The pH of the liquid dispersion medium is preferably
maintained within the range of from about 5.0 to about 7.5 during the size
reduction process. Preferably, the dispersion medium used for the size
reduction process is aqueous.
Effective methods of providing mechanical force for particle size reduction
of naproxen include ball milling, media milling, and homogenization, for
example, with a Microfluidizer.RTM. (Microfluidics Corp.). Ball milling is
a low energy milling process that uses milling media, drug, stabilizer,
and liquid. The materials are placed in a milling vessel that is rotated
at optimal speed such that the media cascades and reduces the drug
particle size by impaction. The media used must have a high density as the
energy for the particle reduction is provided by gravity and the mass of
the attrition media.
Media milling is a high energy milling process. Drug, stabilizer, and
liquid are placed in a reservoir and recirculated in a chamber containing
media and a rotating shaft/impeller. The rotating shaft agitates the media
which subjects the drug to impaction and sheer forces, thereby reducing
the drug particle size.
Homogenization is a technique that does not use milling media. Drug,
stabilizer, and liquid (or drug and liquid with the stabilizer added after
particle size reduction) constitute a process stream propelled into a
process zone, which in the Microfluidizer.RTM. is called the Interaction
Chamber. The product to be treated is inducted into the pump, and then
forced out. The priming valve of the Microfluidizer.RTM. purges air out of
the pump. Once the pump is filled with product, the priming valve is
closed and the product is forced through the interaction chamber. The
geometry of the interaction chamber produces powerful forces of sheer,
impact, and cavitation which are responsible for particle size reduction.
Specifically, inside the interaction chamber, the pressurized product is
split into two streams and accelerated to extremely high velocities. The
formed jets are then directed toward each other and collide in the
interaction zone. The resulting product has very fine and uniform particle
or droplet size. The Microfluidizer.RTM. also provides a heat exchanger to
allow cooling of the product. U.S. Pat. No. 5,510,118, which is
specifically incorporated by reference, refers to a process using a
Microfluidizer.RTM. resulting in sub 400 nm particles.
Using a particle size reduction method, the particle size of naproxen is
reduced to an effective average particle size of less than about 600 nm.
Preferably, the effective average particle size of the nanoparticulate
naproxen is less than about 450 nm, more preferably less than about 300
nm, even more preferably less than about 250 nm, and most preferably less
than about 100 nm. The naproxen particles can be reduced in size in the
presence of a povidone polymer, or the povidone polymer can be added to
the naproxen dispersion following particle size reduction.
Naproxen can be added to a liquid medium in which it is essentially
insoluble to form a premix. The concentration of the naproxen in the
liquid medium can vary from about 5 to about 60%, and preferably is from
about 15 to about 50% (w/v), and more preferably about 20 to about 40%.
The povidone polymer can be present in the premix or it can be added to
the drug dispersion following particle size reduction. The concentration
of the povidone polymer can vary from about 0.1 to about 50%, and
preferably is from about 0.5 to about 20%, and more preferably from about
1 to about 10%, by weight.
The premix can be used directly by subjecting it to mechanical means to
reduce the average naproxen particle size in the dispersion to less than
about 600 nm. It is preferred that the premix be used directly when a ball
mill is used for attrition. Alternatively, naproxen and the povidone
polymer can be dispersed in the liquid medium using suitable agitation,
e.g., a Cowles type mixer, until a homogeneous dispersion is observed in
which there are no large agglomerates visible to the naked eye. It is
preferred that the premix be subjected to such a premilling dispersion
step when a recirculating media mill is used for attrition.
The mechanical means applied to reduce the naproxen particle size
conveniently can take the form of a dispersion mill. Suitable dispersion
mills include a ball mill, an attritor mill, a vibratory mill, and media
mills such as a sand mill and a bead mill. A media mill is preferred due
to the relatively shorter milling time required to provide the desired
reduction in particle size. For media milling, the apparent viscosity of
the premix is preferably from about 100 to about 1000 centipoise, and for
ball milling the apparent viscosity of the premix is preferably from about
1 up to about 100 centipoise. Such ranges tend to afford an optimal
balance between efficient particle size reduction and media erosion.
The attrition time can vary widely and depends primarily upon the
particular mechanical means and processing conditions selected. For ball
mills, processing times of up to five days or longer may be required.
Alternatively, processing times of less than 1 day (residence times of one
minute up to several hours) are possible with the use of a high shear
media mill.
The naproxen particles must be reduced in size at a temperature which does
not significantly degrade naproxen. Processing temperatures of less than
about 30 to less than about 40.degree. C. are ordinarily preferred. If
desired, the processing equipment can be cooled with conventional cooling
equipment. Control of the temperature, e.g., by jacketing or immersion of
the milling chamber in ice water, is contemplated. Generally, the method
of the invention is conveniently carried out under conditions of ambient
temperature and at processing pressures which are safe and effective for
the milling process. Ambient processing pressures are typical of ball
mills, attritor mills, and vibratory mills.
Grinding Media
The grinding media can comprise particles that are preferably substantially
spherical in shape, e.g., beads, consisting essentially of polymeric
resin. Alternatively, the grinding media can comprise a core having a
coating of a polymeric resin adhered thereon.
In general, suitable polymeric resins are chemically and physically inert,
substantially free of metals, solvent, and monomers, and of sufficient
hardness and friability to enable them to avoid being chipped or crushed
during grinding. Suitable polymeric resins include crosslinked
polystyrenes, such as polystyrene crosslinked with divinylbenzene; styrene
copolymers; polycarbonates; polyacetals, such as Delrin.RTM. (E.I. du Pont
de Nemours and Co.); vinyl chloride polymers and copolymers;
polyurethanes; polyamides; poly(tetrafluoroethylenes), e.g.,
Teflon.RTM.(E.I. du Pont de Nemours and Co.), and other fluoropolymers;
high density polyethylenes; polypropylenes; cellulose ethers and esters
such as cellulose acetate; polyhydroxymethacrylate; polyhydroxyethyl
acrylate; and silicone-containing polymers such as polysiloxanes and the
like. The polymer can be biodegradable. Exemplary biodegradable polymers
include poly(lactides), poly(glycolide) copolymers of lactides and
glycolide, polyanhydrides, poly(hydroxyethyl methacylate), poly(imino
carbonates), poly(N-acylhydroxyproline)esters, poly(N-palmitoyl
hydroxyproline) esters, ethylene-vinyl acetate copolymers,
poly(orthoesters), poly(caprolactones), and poly(phosphazenes). For
biodegradable polymers, contamination from the media itself advantageously
can metabolize in vivo into biologically acceptable products that can be
eliminated from the body.
The grinding media preferably ranges in size from about 0.01 to about 3 mm.
For fine grinding, the grinding media is preferably from about 0.02 to
about 2 mm, and more preferably from about 0.03 to about 1 mm in size.
The polymeric resin can have a density from about 0.8 to about 3.0
g/cm.sup.3.
In a preferred grinding process the particles are made continuously. Such a
method comprises continuously introducing naproxen into a milling chamber,
contacting the naproxen with grinding media while in the chamber to reduce
the naproxen particle size, and continuously removing the nanoparticulate
naproxen from the milling chamber.
The grinding media is separated from the milled nanoparticulate naproxen
using conventional separation techniques, in a secondary process such as
by simple filtration, sieving through a mesh filter or screen, and the
like. Other separation techniques such as centrifugation may also be
employed.
Particle Size
As used herein, particle size is determined on the basis of the weight
average particle size as measured by conventional particle size measuring
techniques well known to those skilled in the art. Such techniques
include, for example, sedimentation field flow fractionation, photon
correlation spectroscopy, light scattering, and disk centrifugation. By
"an effective average particle size of less than about 600 nm" it is meant
that at least 90% of the particles, by weight, have a particle size of
less than about 600 nm when measured by the above-noted techniques. In
preferred embodiments, the effective average particle size is less than
about 450 nm, and more preferably less than about 400 nm. The naproxen
particles can also have an effective average particle size of less than
about 300 nm, less than about 250 nm, and less than about 100 nm. With
reference to the effective average particle size, it is preferred that at
least 90%, more preferably at least 95%, and most preferably at least 99%
of the particles have a particle size less than the effective average
particle size. In particularly preferred embodiments essentially all of
the particles have a size less than about 600 nm.
While applicants do not wish to be bound by theoretical mechanisms, it is
believed that the povidone polymer hinders the flocculation and/or
agglomeration of the naproxen particles by functioning as a mechanical or
steric barrier between the particles, minimizing the close, interparticle
approach necessary for agglomeration and flocculation.
Method of Treatment
Yet another aspect of the present invention provides a method of treating a
mammal, including a human, requiring anti-inflammatory, analgesic, or
antipyretic treatment comprising administering to the mammal the
injectable nanoparticulate naproxen formulation of the invention.
Particularly advantageous features of the present invention include that
the pharmaceutical formulation of the invention exhibits unexpectedly
rapid drug absorption upon administration, and produces minimal or no pain
or irritation upon administration. In addition, the injectable formulation
of the invention can provide a high naproxen concentration in a small
volume to be injected. A general protocol for administration comprises a
bolus injection of naproxen, with one continuous fast injection, rather
than a slow infusion of the drug.
Sterile Product Manufacturing
Development of injectable compositions requires the production of a sterile
product. The manufacturing process of the present invention is similar to
typical known manufacturing processes for sterile suspensions. A typical
sterile suspension manufacturing process flowchart is as follows:
##STR2##
As indicated by the optional steps in parentheses, some of the processing
is dependent upon the method of particle size reduction and/or method of
sterilization. For example, media conditioning is not required for a
milling method that does not use media. If terminal sterilization is not
feasible due to chemical and/or physical instability, aseptic processing
can be used.
The following examples are given to illustrate the present invention. It
should be understood, however, that the invention is not to be limited to
the specific conditions or details described in these examples
EXAMPLE 1
The purpose of this example was to evaluate the use of different types of
surface modifiers for the preparation of an injectable nanoparticulate
formulation of naproxen.
The study was conducted by screening eleven surface stabilizers to identify
the most suitable stabilizer for parenteral administration of naproxen.
The dispersions were formulated at 40% solids to 2.4% surface stabilizer.
TABLE 2
______________________________________
Surface Stabilizer
Manufacturer Results
______________________________________
Plasdone C15 .RTM. (polyvinyl- pyrrolidone)
ISP Technologies, Inc.
##STR3##
Kollidon 17PF .RTM. (a polyvinyl- pyrrolidone polymer)
BASF Corp.
##STR4##
Povidone K30 .RTM. (a polyvinyl- pyrrolidone polymer)
ISP Technologies, Inc.
##STR5##
Tyloxapol size reduction >400 nm
Pluronic F68 .RTM.
size reduction >400 nm
(a high molecular
weight poly-
oxyalkylene ether)
Pluronic F108 .RTM.
size reduction >400 nm
(a high molecular
weight poly-
oxyalkylene ether)
Tween 80 .RTM.
ICI Americas
size reduction >400 nm
(a polyoxyethylene
sorbitan fatty
acid ester)
dioctylsulfo-
Ashland Chem. Co.,
size reduction >400 nm
succinate (CAS No.
Columbus, OH
577-11-7; aka
Docusate Sodium)
B20-5000 .RTM.
size reduction >400 nm
(a triblock
copolymer surface
modifier)
B20-5000- Dow Chemical
size reduction >400 nm
sulfonated
(a triblock
copolymer surface
modifier)
lecithin Ashland Chem. Co.,
size reduction >400 nm
(CAS No. Columbus, OH
8002-43-5)
Povidone K30 .RTM.
ISP Technologies,
size reduction >400 nm
and Pluronic
Inc. and BASF Corp.
F108 .RTM.
______________________________________
Only the use of the povidone polymers Plasdone C15, Povidone K30.RTM., and
Kollidon 17PF.RTM. resulted in a nanoparticulate naproxen composition
having an effective average particle size of less than about 400 nm.
EXAMPLE 2
The purpose of this example was to determine the rates of absorption for
intravenously and intramuscularly administered naproxen.
The plasma concentration of naproxen (.mu.g/ml) in rabbits after
administration of 15 mg/kg by either the IV or IM routes versus time in
hours was determined. The method used for quantification of naproxen in
rabbit plasma was modified from a procedure by Shimek et al., Journal of
pharm. Sci., 15:436-439 (1982).
For IM administration, the mean peak plasma level concentration (C.sub.max)
of 45.+-.9 .mu.g/ml was reached at two hours. The absorption after IM
injection was rapid with a mean plasma concentration of 23.5.+-.5.1
.mu.g/ml at 30 minutes after injection. At twelve hours post injection,
plasma concentrations were still measurable at 5.2.+-.3.4 .mu.g/ml.
Pharmacokinetic Analysis: The area-under-curve value (AUC) (i.e., plasma
-concentration time curve) calculations for the IM and IV routes were
287.1 .mu.g/ml.multidot.hr and 212.0 .mu.g/ml.multidot.hr, respectively.
Mean clearance was calculated to be 3.4 ml/min after IM administration and
5.1 ml/min following IV administration. The calculated T.sub.1/2 (the
time period in which the maximum plasma concentration drops by half)
following IM administration was 6.9 hours, and 7.0 hours following IV
administration.
EXAMPLE 3
The purpose of this example was to demonstrate the feasibility of using a
Microfluidizer.RTM. for aseptically producing an injectable formulation of
a naproxen colloidal dispersion.
A Microfluidizer.RTM., Model No. M110EH (Microfluidics Corp.), was
successfully used to produce a sterile colloidal dispersion of naproxen
suitable for injection. The naproxen slurry was heat sterilized prior to
microfluidizing.
EXAMPLE 4
The purpose of this example was to determine the potential local irritation
of an injectable nanoparticulate naproxen formulation when administered
intramuscularly to rats. This information correlates to the irritation or
pain experienced upon administration of the formulation.
Test Formulation
Injectable nanoparticulate naproxen having a concentration of 489 mg/ml was
used, comprising 489 mg/ml naproxen, 40 mg/ml of ISP Plasdone.TM. C15, 1.9
mg/ml methylparaben (preservative), and 0.2 mg/ml propylparaben. Dosages
of 49 and 134 mg/kg were administered intramuscularly. The intramuscular
route was chosen because it is a possible route of administration to
human. The test and control articles were stored at room temperature and
protected from light.
Test animals
Twenty male Albino rats (Sprague-Dawley Crl:CD.RTM.) were used for the
study, obtained from Charles River. The animals were laboratory bred and
were experimentally naive at the outset of the study. Animals selected for
use were as uniform in age and weight as possible. they were approximately
7-8 weeks of age, and their body weights ranged from 210.7 to 247.0 gm.
Each animal was identified by a unique number via an ear tag. All animals
were acclimated to laboratory conditions for approximately 12 days prior
to study initiation, and the animals were housed individually in
stainless-steel cages.
PMI Feeds, Inc..RTM., Certified Rodent Chow was available ad libitum via
food hoppers. No contaminants are known to be present in the certified
diet that would interfere with the results of the study. Tap water was
available ad libitum via automatic watering device or water bottle. The
water was routinely analyzed for contaminants. No contaminants are known
to be present in the water that would interfere with the results of the
study.
All animals were kept in one room and with no additional studies or other
species housed in the same room. The room was well ventilated (>10 air
changes per hour) with 100% fresh air (no air recirculation). A 12-hour
light/12-hour dark photoperiod was maintained. Room temperature and
relative humidity were set to be maintained between 22.+-.3.degree. C. and
40 to 70%, respectively.
Administration Protocol and Methods
The twenty test animals were assigned to treatment groups as shown in Table
3 below. Each animal received a single intramuscular injection of the test
article and the vehicle in distinct previously shaven sites of
contralateral legs: thigh muscle of the right and left hind legs,
respectively. Prior to the day of dosing (designated Day 1 of the study),
all animals were fasted overnight. Following dosing, animals were returned
to their cages and subsequently provided with hoppers containing food. The
animals were evaluated for changes in clinical signs and body weight and
the injection sites were examined for any local reaction. Ten animals each
were sacrificed at approximately 48 and 96 hours after the IM injection
and the injection site areas removed and processed for histopathological
examination.
TABLE 3
______________________________________
Treatment Groups
Number of Dose Dose Vol.
Day of
Group Males Treatment (mg/kg)
(ml/kg)
Sacrifice
______________________________________
1 5 Control 0 0.1 3
Nanonaproxen
49 0.1
2 5 Control 0 0.1 5
Nanonaproxen
49 0.1
3 5 Control 0 0.275 3
Nanonaproxen
134 0.275
4 5 Control 0 0.275 5
Nanonaproxen
134 0.275
______________________________________
Antemortem Procedures
Animals were observed once daily prior to dosing. During the study, each
animal was observed once each morning and afternoon for changes in general
appearance and behavior. In addition, the injection sites were examined
daily thereafter for local reactions. The severity of any injection site
observation was graded and if possible measured (length, width, and
height). Body weights were measured prior to dosing and at sacrifice.
1. Clinical Observations and Mortality
Twice daily individual clinical observations are presented in Table 4. No
animals died and no treatment-related clinical signs were seen in animals
given 49 mg/kg of nanoparticulate naproxen by intramuscular injection. At
a dose of 134 mg/kg/treatment-related signs such as chromorhinorrhea,
pallor, rough coat, and some chromodacryorrhea and brown staining were
observed.
TABLE 4
__________________________________________________________________________
Clinical Observations
Animal
Test Article
No. Clinical Observations*
__________________________________________________________________________
Nanoparticulate
311M
Days 1-3: normal
Naproxen;
312M
Days 1-3: normal
49 mg/kg
313M
Days 1-3: normal
For 3 day test
314M
Days 1-2: normal
period Day 3: abrasion neck right side; stain red neck right side;
scab scapula
right
315M
Days 1-3: normal
Nanoparticulate
321M
Days 1-5: normal
Naproxen;
322M
Days 1-5: normal
49 mg/kg
323M
Day 1: normal
For 5 day test
Day 2: slight bluish color at injection site 2
period Days 3-5: normal
324M
Days 1-4: normal
Day 5: dehydrated; scab at injection site on right hind limb
325M
Days 1-5: normal
Nanoparticulate
331M
Day 1: normal
Naproxen; Days 2-3: infrequent stool
134 mg/kg Day 3: chromorhinorrhea, pallor
For 3 day test
332M
Day 1: normal
period Days 2-3: infrequent stool; chromorhinorrhea; pallor; rough
coat
Day 3: chromodacryorrhea-both; brown-stained scrotum
333M
Day 1: normal
Days 2-3: infrequent stool
Day 3: chromorhinorrhea; pallor; dehydrated; scab at right
injection
site
334M
Day 1: normal
Days 2-3: infrequent stool; chromorhinorrhea; wet coat pelvic
region
Day 3: pallor; scabs at both injection sites left and right
hind limbs
335M
Day 1: normal
Days 2-3: infrequent stool
Day 3: chromodacryorrhea both; chromorhinorrhea; dehydrated;
pallor; diarrhea; dark stool
Nanoparticulate
341M
Day 1: normal
Naproxen; Days 2-4: chromorhinorrhea
134 mg/kg Days 2-5: infrequent stool; pallor
For 5 day test
Day 3: brown-stained forefeet
period Days 3-5: rough coat
Day 4: prostrate
Day 5: dehydrated; scab at injection sites on right hand limb
342 Day 1: normal
Day 2: chromorhinorrhea
Days 2-3: infrequent stool
Days 3-5: rough coat; pallor
Days 4-5: scabhead
Day 5: scab at injection sites on left hand limb
343M
Day 1: normal
Days 2-5: infrequent stool
Days 3-5: piloerection; rough coat; dehydrated; pallor
344M
Day 1: normal
Day 2: loose stool; chromorhinorrhea
Days 2-3: infrequent stool
Days 2-4: rough coat
Day 5: scabs at injection sites bilaterally
345M
Day 1: normal
Days 2-5: infrequent stool; chromorhinorrhea; pallor
Day 3: rough coat; chromodacryorrhea both
Days 3-5: brown-stained forefeet
Day 5: dehydrated; scabs at injection sites on hind
__________________________________________________________________________
limbs
*Findings exclude mechanical artifacts (clipper abrasions).
2. Body Weight
Individual and group mean body weights are presented in Table 5. The Day 3
low-dose group (49 mg/kg) was inadvertently not fasted for necropsy and,
therefore, showed a much larger weight gain than the fasted low-dose group
sacrificed on Day 5. However, animals in the high-dose group (134 mg/kg)
sacrificed on Days 3 (also, inadvertently not fasted) or 5 showed an
overall average weight loss that was considered to be treatment related.
TABLE 5
______________________________________
Individual and Group Mean Body Weights (g)
Animal
Treatment No. Day 1 Day 3*
Day 5
______________________________________
Nanoparticulate Naproxen;
311M 210.7 251.5
49 mg/kg 312M 219.4 256.6
313M 224.5 260.9
314M 234.7 271.8
315M 237.3 273.0
mean 225.3 262.8
.+-.SD .+-.11.0 .+-.9.4
Nanoparticulate Naproxen;
321M 218.9 233.5
49 mg/kg 322M 216.8 222.4
323M 223.4 229.5
324M 234.6 249.1
325M 241.9 259.3
mean 227.1 238.8
.+-.SD .+-.10.8 .+-.15.1
Nanoparticulate Naproxen;
331M 215.2 203.2
134 mg/kg 332M 216.6 210.1
333M 226.7 211.0
334M 228.0 216.3
335M 247.0 227.3
mean 226.7 213.6
.+-.SD .+-.12.7 .+-.9.0
Nanoparticulate Naproxen;
341M 216.1 192.1
134 mg/kg 342M 213.0 184.5
343M 226.3 189.7
344M 228.3 208.5
345M 241.5 209.2
mean 225.0 196.8
.+-.SD .+-.11.3 .+-.11.3
______________________________________
*Terminal body weight from unfasted animals.
3. Injection Site Evaluation
Individual and group mean dermal irritation (erythema/eschar) and (edema)
are presented in Tables 6 and 7, respectively. No erythema/eschar or edema
responses were noted in any of the animals (indicated by "0" in Tables 6
and 7).
TABLE 6
______________________________________
Individual and Group Mean Dermal Irritation (Erythema or Eschar)
Scores
Animal
Treatment No. Day 2 Day 3 Day 4 Day 5
______________________________________
Control 311M 0 0
312M 0 0
313M 0 0
314M 0 0
315M 0 0
mean 0 0
.+-.SD .+-.0 .+-.0
Nanoparticulate
311M 0 0
Naproxen; 49 mg/kg
312M 0 0
313M 0 0
314M 0 0
315M 0 0
mean 0 0
.+-.SD .+-.0 .+-.0
control 321M 0 0 0 0
322M 0 0 0 0
323M 0 0 0 0
324M 0 0 0 0
325M 0 0 0 0
mean 0 0 0 0
.+-.SD .+-.0 .+-.0 .+-.0 .+-.0
Nanoparticulate
321M 0 0 0 0
Naproxen; 49 mg/kg
322M 0 0 0 0
323M 0 0 0 0
324M 0 0 0 0
325M 0 0 0 0
mean 0 0 0 0
.+-.SD .+-.0 .+-.0 .+-.0 .+-.0
Control 331M 0 0
332M 0 0
333M 0 0
334M 0 0
335M 0 0
mean 0 0
.+-.SD .+-.0 .+-.0
Nanoparticulate
331M 0 0
Naproxen; 332M 0 0
134 mg/kg 333M 0 0
334M 0 0
335M 0 0
mean 0 0
.+-.SD .+-.0 .+-.0
control 341M 0 0 0 0
342M 0 0 0 0
343M 0 0 0 0
344M 0 0 0 0
345M 0 0 0 0
mean 0 0 0 0
.+-.SD .+-.0 .+-.0 .+-.0 .+-.0
Nanoparticulate
341M 0 0 0 0
Naproxen; 342M 0 0 0 0
134 mg/kg 343M 0 0 0 0
344M 0 0 0 0
345M 0 0 0 0
mean 0 0 0 0
.+-.SD .+-.0 .+-.0 .+-.0 .+-.0
______________________________________
TABLE 7
______________________________________
Individual and Group Mean Dermal Irritation (Edema) Scores
Treatment Animal No.
Day 2 Day 3 Day 4 Day 5
______________________________________
Control 311M 0 0
312M 0 0
313M 0 0
314M 0 0
315M 0 0
mean 0 0
.+-.SD .+-.0 .+-.0
Nanoparticulate
311M 0 0
Naproxen; 49 mg/kg
312M 0 0
313M 0 0
314M 0 0
315M 0 0
mean 0 0
.+-.SD .+-.0 .+-.0
Control 321M 0 0 0 0
322M 0 0 0 0
323M 0 0 0 0
324M 0 0 0 0
325M 0 0 0 0
mean 0 0 0 0
.+-.SD .+-.0 .+-.0 .+-.0
Nanoparticulate
321M 0 0 0 0
Naproxen; 49 mg/kg
322M 0 0 0 0
323M 0 0 0 0
324M 0 0 0 0
325M 0 0 0 0
mean 0 0 0 0
.+-.SD .+-.0 .+-.0 .+-.0 .+-.0
control 331M 0 0
332M 0 0
333M 0 0
334M 0 0
335M 0 0
mean 0 0
.+-.SD .+-.0 .+-.0
Nanoparticulate
331M 0 0
Naproxen; 332M 0 0
134 mg/kg 333M 0 0
334M 0 0
335M 0 0
mean 0 0
.+-.SD .+-.0 .+-.0
control 341M 0 0 0 0
342M 0 0 0 0
343M 0 0 0 0
344M 0 0 0 0
345M 0 0 0 0
mean 0 0 0 0
.+-.SD .+-.0 .+-.0 .+-.0 .+-.0
Nanoparticulate
341M 0 0 0 0
Naproxen; 342M 0 0 0 0
134 mg/kg 343M 0 0 0 0
344M 0 0 0 0
345M 0 0 0 0
mean 0 0 0 0
.+-.SD .+-.0 .+-.0 .+-.0 .+-.0
______________________________________
Postmortem Procedures
All animals were terminated by CO.sub.2 asphyxiation and exsanguination.
Gross necropsy was limited to examination of the injection sites. No
treatment-related effects were observed as all injection sites (muscle)
were normal. One animal (#333) had a single red subcutaneous focus above
the muscle injection site that probably corresponded to hemorrhage.
Injection site scabs noted on the twice daily clinical observations
generally corresponded to dried blood. Although no internal gross
examination was performed, two high-dose animals (#'s 332 and 333) were
observed to have severely distended stomachs filled with fluid and gas
when they were terminated by exsanguination. These observed findings were
considered to be treatment related.
Conclusion
No dermal irritation was observed following single-dose intramuscular
administration of injectable nanoparticulate naproxen at doses of 49 mg/kg
and 134 mg/kg, in comparison to the control animals. Similarly, no
treatment-related clinical signs were observed at doses of 49 mg/kg. At a
dose of 134 mg/kg, the following clinical signs were observed:
chromorhinorrhea, pallor, rough coat, some chromodacryorrhea, and brown
staining.
At necropsy, no treatment-related gross findings at the injection sites
were observed. Similarly, histopathological examination of the injection
sites revealed no treatment-related effects.
It will be apparent to those skilled in the art that various modifications
and variations can be made in the compositions, methods, and uses of the
present invention without departing from the spirit or scope of the
invention. Thus, it is intended that the present invention cover the
modifications and variations of this invention provided they come within
the scope of the appended claims and their equivalents.
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